Nuclear localization of LDL receptor-related protein 1B in mammary gland carcinogenesis
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LRP1B intracellular domain is released and transported to the nucleus; however, pathological consequences of this nuclear transport are largely unclear. We aimed to unravel the pathobiological significance of nuclear localization of LRP1B intracellular domain in mammary gland carcinogenesis. Immunohistochemical staining using antibodies for LRP1B intracellular domain was performed to determine LRP1B expression in 92 invasive ductal breast carcinomas. LRP1B immunoreactivity was detected in the surface membrane and cytoplasm of 60 of 92 invasive ductal carcinomas and in the nucleus of 15 of 92 carcinomas. Nuclear LRP1B was significantly associated with poor patient prognosis, particularly luminal A type breast cancer, where it was significantly related to nodal metastasis. Doxycycline-dependent nuclear expression of LRP1B intracellular domain was established in cultured breast cancer cells. Enforced nuclear expression significantly increased Matrigel invasion activity in MCF-7 and T47D luminal A breast cancer cells. Moreover, enforced nuclear expression of LRP1B intracellular domain facilitated MCF-7 cells growth in mammary fat pad of nude mice, which was supplemented with estrogen. Comprehensive microarray-based analysis demonstrated that nuclear expression of LRP1B intracellular domain significantly increased long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression, which facilitates breast cancer invasion with poor prognosis. Nuclear-localized LRP1B intracellular domain promoted breast cancer progression with poor prognosis, possibly through the NEAT1 pathway. Nuclear transport of LRP1B intracellular domain could be a therapeutic target for breast cancer patients.
Nuclear LRP1B was significantly associated with poor patient prognosis.
Nuclear LRP1B increased Matrigel invasion activity of breast cancer cells.
Nuclear expression of LRP1B intracellular domain increased NEAT1 expression.
KeywordsLRP1B Nuclear localization Breast cancer Prognosis NEAT1
This study was supported by grants from the Ministry of Education of Japan (grant nos. KAKEN 15K08361, 15K19051, and 17K15642).
Compliance with ethical standards
Paraffin-embedded tissues surgically resected from patients with breast cancer were retrospectively used after diagnosis. The need for written informed consent was waived by the Institutional Review Board of the Gifu University Graduate School of Medicine. Instead, the Institutional Review Board requested us to inform the patients that they could refuse the use of their tissue specimens for this study if they did not want to participate in the present study. The experimental protocol to obtain the antibodies was approved by the Animal Care Committee of Gifu University. The present study was conducted in accordance with the ethical standards of the Helsinki Declaration in 1975, after approval of the Institutional Review Board of the Gifu University Graduate School of Medicine (specific approval number 25–81).
Conflict of interest
The authors declare that there are no conflicts of interest.
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